This project will generate new methods of organic synthesis and fully test the methods in the synthesis of biologically active natural products and analogs. The theme is the activating and directing effects of transition metals. The development of new methodology and application in formation of complex structures continues to be part of a powerful approach to the development of new drugs. Transition metals offer the opportunity to carry out delicate and selective carbon-carbon coupling reactions, appropriate for the stereo-defined and highly functionalized targets. Two aspects of organo-transition metal chemistry will be developed. Rearrangements of metal-coordinated vinyl-carbenes is a theme which begins with carbene-metal reactions with alkynes to give quinone derivatives and leads to intriguing catalytic rearrangements of cyclopropenes into more general series of aromatic structures. Direct interaction of vinyl carbenes with metals will lead via the same pathways to general aromatic compounds, and may give direct evidence for the multi-step pathway involved. In the second area, palladium will be used to promote the formation of heterocyclic rings, with concomitant coupling with CO and other carbon units as chain extension steps. Specific application in the total synthesis of tetronomycin as well as partial synthesis of other antibiotics are proposed. A representative anthraquinone related to the natural antitumor agents will be constructed using the vinyl-carbene/metal technology. In addition, the final stages of the synthesis of granaticin, a potent inhibitor of protein and nucleic synthesis, will be completed with an application of organo-nickel intermediates.